Project Summary The largest US cancer health disparity exists in prostate cancer (PC), with African American (AA) men having a 1.6-fold increased risk of developing PC; younger age and more advanced stage at diagnosis; increased risk for recurrence after radical prostatectomy; and a 2.5-fold increased mortality rate relative to Caucasian American (CA) men. Socioeconomic and environmental factors do not fully account for these disparities. Interestingly, PC is not more aggressive in Hispanic populations than in CA, despite similar socioeconomic disparities frequently burdening Hispanic and AA men. This observation further supports that the higher aggressiveness of AA PC is, at least in part, linked to genetic/intrinsic factors. Thus, there is an unmet need to identify actionable targets in AA PC in order to develop more effective therapeutics and, ultimately, improve clinical outcomes for AA PC patients. Unfortunately, most preclinical studies are performed in PC cell lines and patient-derived xenografts (PDXs) isolated from patients of Caucasian origin. Our Minority PDX Development and Trial Center (M-PDTC) provides a unique opportunity to help address these racial/ethnic disparities. Findings from both our group and others in the field unequivocally argue that there are biological differences between AA and CA PC that are intrinsic to PC cells. Unfortunately, most preclinical studies are performed in PC cell lines and patient-derived xenografts (PDXs) isolated from patients of Caucasian origin. Thus, we propose to leverage the high numbers of minority cancer patients at Baylor College of Medicine (BCM) in order to generate and utilize innovative PC PDX models of diverse racial/ethnic minority origin, which will broaden our understanding of the molecular basis of the disease as well as expedite the drug discovery process. The work proposed here will result in the development of over 100 novel PC PDXs, including at least 60 AA PC PDXs. We will utilize whole exome sequencing (WES), global RNA-sequencing (RNA-seq), quantitative proteomic (qKiP) and metabolomic profiling to uncover novel, effective treatment strategies against AA PC. As controls, we will also study PDXs from Hispanic and CA men. The results of this study, in particular the multi-Omics datasets, will assist the entire scientific community delineate the molecular underpinnings of AA PC. We will conduct preclinical trials of promising NCI-IND drugs, selected based on results of our Preliminary Studies. We have now found increased kinase activity in AA PC patient samples and PDXs and hypothesize that targeting these signaling axes can improve clinical outcomes for AA PC patients. Our preclinical trials using newly generated PDXs from minority patients will allow us to 1) identify predictive biomarkers of treatment response related to the PI3K/mTOR, MAPK, other kinase and the DNA damage response (DDR) pathways, 2) decipher mechanisms of resistance, and 3) subsequently, design combinatorial therapies that will enhance anti-tumor activity against AA PC.